New Findings on Beta-Cells and Insulin Resistance

Researchers of the Max Delbrück Center (MDC) have gained new insights into how the insulin-producing beta-cells of the body adapt to an increased demand of this hormone during insulin resistance.

In this condition the body produces insulin but cannot use it effectively and it can lead to the onset of type-2 diabetes. Dr. Matthew Poy`s research group identified several components of a network within the microRNA (miRNA) pathway which help beta-cells to meet changes in the insulin demand of the body.

They now showed for the first time how beta cells make use of this pathway to control proliferation and insulin release upon restoration of insulin sensitivity in obese mice (Cell Metabolism)*.

Insulin is a hormone produced by the beta cells of the pancreas to regulate circulating blood glucose for energy. Glucose enters the bloodstream after a meal leading to an increase in insulin concentrations in the body which directs glucose uptake by muscle and fat cells. While the precise cause of insulin resistance is not known, elevated levels of the hormone (hyperglycemia) remain in circulation, do to a loss of insulin action in its target tissues. As a result, blood glucose levels remain elevated exacerbating the metabolic consequences of hyperglycemia.

As insulin resistance progresses over time, islet beta-cells are very dynamic in nature and can adapt to this metabolic stress by proliferating in order to accommodate the increased demand for insulin. Since all of the body’s cells need glucose for energy, the beta-cells of the pancreas continually produce more insulin to ensure proper glucose homeostasis. This process can go on for years without notice up to the point where type-2 diabetes finally develops.

Dr. Poy and his colleagues carefully addressed how beta cells make use of the microRNA (miRNA) pathway to proliferate and secrete insulin during changes in insulin sensitivity. “Recent evidence has shown that the miRNA pathway is an important regulator of gene expression in response to metabolic stress”, Dr. Poy pointed out. “It also has been known that the miRNA pathway has an essential role in the proliferation of beta-cells, however the extent of its contribution is unclear”, he said.

MicroRNAs are small ribonucleic acidsmolecules with about 22 nucleotides that are known transcriptional products of DNA. Only within the last 10 years, researchers have discovered that microRNAs play an important role in virtually all mammalian cells. While their precise function remains unclear, miRNAs have been established as significant regulators of gene expression. That is, miRNAs control which proteins and how much of a protein cells secrete.

Sudhir G. Tattikota, Thomas Rathjen and Dr. Poy now have identified two different miRNAs with independent roles in the insulin metabolism including miRNA-184 (miR-184). The researchers could show that this microRNA is silenced as insulin resistance develops – in mice as wells as in humans who have acquired type-2 diabetes.

As a result of the silencing of this miRNA, expression of targeted genes including Argonaute2 (Ago2), are upregulated in the beta cells. Ago2 belongs to the Argonaute family of proteins that are known to guide the miRNAs to their target genes. According to the researchers this protein plays a key role during insulin resistance by facilitating beta-cell proliferation and the production of more insulin to compensate for insulin resistance.

The researchers worked with obese mice that had already developed insulin resistance. Obesity is one among others a risk factor for the developing of diabetes type-2. When the researchers deleted Ago2 specifically in the beta cells of the pancreas in these mice, the compensatory proliferation of the beta-cells was reduced. “This underlines the integral role of Ago2 and the miRNA pathway in this process”, Dr. Poy and his colleagues stressed.

How a Low-carbohydrate diet restores function of beta-cells in obese mice Previous studies in mice and humans have shown that a high fat, low carbohydrate or “ketogenic” diet can improve insulin sensitivity. The researchers showed that obese mice fed this diet restored the function of miR-184, thereby controlling both beta cell proliferation as well as the release of insulin by targeting Ago2 as well as another gene (Slc25a22) respectively.

With this study, the researchers have shown that targeting of Ago2 by miRNA-184 is an essential component of the compensatory response to regulate proliferation of beta cells according to insulin sensitivity. Dr. Poy: “Our observations on the effects of the ketogenic diet on microRNA function in the beta-cell unify several poorly understood mechanisms and reinforce the potential in studying the role of small RNAs in physiologic stresses”. He and his colleagues hope that research on the miRNA pathway should bring clarity in understanding how the network of small RNAs contribute to maintaining essential metabolic processes and how their failure ultimately leads to disease.

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